R-1579类似物的合成及其二肽基肽酶Ⅳ(DPP-Ⅳ)抑制活性

Synthesis and DPP-Ⅳ inhibitory activities of R-1579 analogues

目的设计合成R-1579的类似物,并对其体外DPPⅣ-抑制活性进行评价。方法以取代苯甲醛和丙二腈为原料经缩合、与脒环合、氧化及催化氢化等反应制得目标化合物;选择其中部分化合物测试其DPPⅣ-抑制活性。结果与结论共制得18个目标化合物,经过1H-NMR、MS确证结构,其中化合物8h、10 c及10d的活性优于阳性对照R-1579。

R-1579,developed by Roche Ltd,showed inhibition of DPP-Ⅳ activity.Eighteen R-1579 analogues were prepared to study their structure-activity relationship（SAR）.Cyclization between amidines and aryl methylidenem-olonitriles give intermediates 5,which was oxidized by DDQ and catalytic hydrogenation to afford target compounds 7a-7c and 8a-8i,or was acylated from 7a give 11a-11b;Compound 5 that have 2-methylene group of pyrimidine ring can also be oxidated by KMnO4 to give ketone 9,then underwent catalytic hydrogenation to afford target compounds 10a-10d.Moreover,the structure of all target compounds were confirmed by 1H-NMR and MS spectra.In comparison with R-1579,all target compounds were subjected to the DPP-Ⅳ inhibition activity test.The results demonstrated that almost all compounds shows good inhibition of DPP-Ⅳ about 20.2%-66.8% at 0.1 μmol·L-1 except 7b,11a and 11b,reserved 6-（2,4-dichlorophenyl）-and modified 2-phenyl-group of pyrimidine ring has the best activity among them.Compounds 8h,10c and 10d（IC50=0.074,0.107,0.069 μmol·L-1） show better DPP-Ⅳ inhibition activity than R-1579.